This invention is in the field of genetic polymorphisms, particularly polymorphisms in a diacylglycerol acyltransferase gene.
Triacylglycerols are quantitatively the most important storage form of energy in eukaryotes. Triglyceride synthesis is thought to occur primarily through acyl CoA:diacylglycerol transferase (DGAT), a microsomal enzyme. Diacylglycerol acyl-transferase (DGAT; acyl CoA:diacylglycerol acyltransferase; EC 2.3.1.20) is a ubiquitous enzyme that catalyzes the synthesis of triglycerides by adding a fatty acid to diacylglycerol. DGAT plays a fundamental role in the metabolism of cellular diacylglycerol, and is important in higher eukaryotes for physiologic processes involving triacylglycerol metabolism, such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, and lactation. Cases et al. (1998) Proc. Natl. Acad. Sci. USA 95:13018-13023.
Abnormal fat storage causes, or is related to, a variety of debilitating, and often lethal, conditions. As one example, obesity, generally defined as a condition of being 20% or more over ideal body weight, affects an estimated 34 million Americans, and is a major cause of death in the Unites States. Morbid obesity, a much more severe form of obesity in which a person is 100 or more pounds overweight, affects an estimated four million Americans. One important consequence of obesity is maturity-onset (Type II) diabetes. Obesity is also linked to, or increases the risk of, hypertension, atherosclerosis, and myocardial infarction, as well as other serious disorders. Hypertension alone affects approximately 50 million Americafns, and increases the risk of heart disease and stroke, which are leading causes of death among Americans. The profound negative health and social consequences of obesity have provided the impetus for development of a large number of drugs for control of this condition. Bray and Greenway (1999) Endocrinol. Rev. 20:805-875. While several genes and mutations have been identified that contribute to obesity and other common metabolic disorders, they represent a small fraction of the genetic causes of obesity. Chagnon et al. (2000) Obesity Res. 8:89-117; and Barsh et al. (2000) Nature 404:644-651.
Despite advances in detecting mutations and genes associated with obesity, obesity continues to exert adverse effects on human health. Thus, there is a need in the art for identification of additional information regarding genes and gene mutations associated with obesity. Such information is crucial for identifying individuals who have a propensity toward becoming obese, and for identifying new therapeutic targets for control of obesity. The present invention addresses this need by providing polymorphisms associated with conditions associated with DGAT activity, including, e.g., obesity.
The present invention provides an isolated polynucleotide comprising a polymorphic nucleotide sequence from a diacylglycerol acyltransferase (DGAT) gene. The polymorphism may be in a coding or non-coding portion of the gene. In some embodiments, polymorphisms are associated with a condition associated with DGAT activity. In some of these embodiments, the polymorphism is associated with a condition relating to abnormal fat storage. In particular embodiments, polymorphisms are associated with obesity. Isolated polynucleotides comprising one or more polymorphisms in a DGAT gene that are associated with a condition associated with DGAT activity are useful in diagnostic assays.
Accordingly, the invention further provides diagnostic assays for detecting the presence in a nucleic acid sample of a polymorphism in a DGAT gene that is associated with a condition associated with DGAT activity. Diagnostic assays are useful in predicting an individual""s likelihood of developing a condition associated with DGAT activity. Thus, the invention further provides methods of detecting a propensity in an individual of developing a condition associated with DGAT activity. The invention further provides methods for genetically diagnosing in an individual a condition associated with DGAT activity. These methods generally involve detecting in a nucleic acid sample derived from an individual a DGAT polymorphism associated with a condition associated with DGAT activity. In some embodiments, diagnostic assays are conducted using a microarray comprising a DGAT polymorphic nucleic acid molecule.
Detection of DGAT polymorphisms associated with a condition associated with DGAT activity allows selection of a treatment plan that is most likely to be effective in treating the condition. Thus, the invention further provides methods for treating an individual clinically diagnosed with a condition associated with DGAT activity, generally comprising detecting a DGAT polymorphism associated with a condition associated with DGAT activity, and selecting a treatment plan that is most effective for individuals clinically diagnosed as having a condition associated with DGAT activity. Detection of DGAT polymorphisms associated with a condition associated with DGAT activity also allows one to predict a patient""s likelihood to respond to a specific drug treatment. Thus, the invention further provides methods of predicting a patient""s likelihood to respond to a specific drug treatment for a condition associated with DGAT activity.
The invention further provides an array of nucleic acid molecules immobilized on a solid surface, where at least one of the nucleic acid molecules comprises a DGAT polymorphic nucleic acid molecule. The nucleic acid arrays of the invention allow rapid detection of hybridizing nucleic acid molecules, in a nucleic acid sample from an individual, of a DGAT polymorphism associated with a condition relating to abnormal fat storage.
The invention further provides isolated polymorphic DGAT polypeptides, as well as antibodies specific for polymorphic DGAT polypeptides. The specific antibodies are useful in assays for detecting the presence of a polymorphic DGAT polypeptide in a biological sample. In carrying out these detection assays, antibodies bound to a solid support may be used. Thus, the invention further provides assay devices comprising antibodies specific for polymorphic DGAT polypeptides, where the antibodies are attached to a solid support.
These and other aspects of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.